Processes and apparatus for extraction of active substances and enriched extracts from natural products

ABSTRACT

Processes for preparing extracts of natural products such as plant material, and for preparing purified extracts from crude extracts of natural products, by extraction with hot gas. Apparatus suitable for use in preparing extracts of natural products are also described.

FIELD OF THE INVENTION

[0001] The present invention relates to processes for preparing extractsof natural products, such as plant material, and for preparingpurified-extracts from crude extracts of natural products by extractionwith hot gas, and also to apparatus suitable for use in preparingextracts of natural products.

BACKAROUND TO THE INVENTION

[0002] The therapeutic activity of plant medicines is attributed to theactive constituents which they contain. In some cases the intrinsicactivity of natural products has been linked to specific chemicalspecies, but in other cases the activity of the plant medicine isconsidered to be due to a combination of constituents acting in concert.In most plant materials the active constituent is present in varyingproportions. For example, vincristine is an alkaloid present in theaerial parts of Vinca roseaea at concentrations of less than 0.1% of thedried biomass. In the case of cannabis resin, the concentration ofactive constituent may be more than 60% w/w of resin (hashish). Whateverthe concentration in biomass, it is convenient to extract specificconstituents, or produce an enriched extract, which can be thenformulated into conventional dosage forms for ease of administration.

[0003] Methods of extraction which have been used to separateconstituents of plant medicines and to produce enriched extracts includemaceration, decoction, and extraction with aqueous and non-aqueoussolvents, distillation and sublimation.

[0004] Maceration (also known as simple maceration) is defined as theextraction of a drug in a solvent with daily shaking or stirring at roomtemperature. After a defined period the spent, solid material isseparated from the solution (macerate). Variation on the method includesagitation of the macerate and the use of temperatures up toapproximately 50° C. The method was formerly used for the preparation oftinctures and extracts from low-density plant materia medica, usingvarious strengths of ethanol as the extraction solvent.

[0005] Decoction has been used since antiquity for the preparation oftraditional medicines. In traditional Chinese medicine it is customaryto place the quantity of herbs required for one day's treatment into avessel to which hot or boiling water is added. The vessel is then raisedto boiling point and allowed to simmer for 1½ hours (sometimes longer).The decoction so produced is allowed to cool, separated from solidparticles, and the decoction is used as the dosage form for oraladministration.

[0006] Maceration and decoction rely on a short diffusion path. Inactiveconstituents such as lecithins, flavinoids, glycosides and sugars mayact to solubilise constituents which, in the pure state, are reallysoluble in the solvent. A disadvantage of maceration and decoction withwater or low concentrations of ethanol is that a large quantity of inertmaterial (ballast) that does not have therapeutic value is extracted.Ballast may consist of plant cell constituents including, but notlimited to, fats, waxes, carbohydrates, proteins and sugars. This maycontribute to microbiological spoilage if the product is not usedpromptly. If dried, the extracts so produced tend to be hygroscopic anddifficult to formulate. The ballast may also affect the way in which theactive constituents are absorbed from the finished dosage form.

[0007] Maceration and decoction are still widely used in situationswhere the balance of convenience inherent in the low technology involvedoutweighs the lack of precision in such technology in the context ofpharmaceutical production. In the case of macerates and percolates,solvents may be removed by evaporation at temperatures below 100° C. andpreferably below 60° C.

[0008] A wide range of processes based on the use of non-aqueoussolvents to extract the constituents from plants have been used in theprior art. The solvents employed may be miscible with water or waterimmiscible and vary in solvent power according to the concept of E°,which is familiar in the context of chromatography.

[0009] Traditionally, ethyl alcohol in various concentrations has beenused to extract active substances from plant materials. Tinctures arealcoholic solutions produced in this way and tinctures of plantmaterials are described in all major pharmacopoeias. Where the finalconcentration of alcohol is greater than approximately 20% by volume,the tincture remains microbiologically stable and such tinctures havebeen widely used in compounding prescriptions. Ethanol extractssubstances such as glycosides, flavinoids and alkaloid salts which areexamples of classes of compound known to be biologically active. It alsoextracts considerable amounts of plant pigment, such as chlorophyll andcarotenoids. By using higher alcoholic strengths lipid-soluble materialmay be extracted. Tinctures contain less ballast than macerates ordecoctions, but are still complex mixtures of plant constituents. Wherethe presence of alcohol is not required the tincture can be evaporatedto produce extracts. All pharmacopoeias contain liquid and solidextracts produced in this way.

[0010] Lipid solvents with a high E° value have been used to extractlipid soluble constituents from biomass. Examples are chlorinatedsolvents such as dichloromethane, chloroform and carbontetrachloride,hexane, ether, fluorinated hydrocarbons and supercritical fluidextraction with agents such as carbon dioxide.

[0011] Chlorinated solvents are no longer used commercially forextraction of plant biomass because they are themselves toxic and forpharmaceutical use the solvent must be removed. They are, however,reactive and can also result in the production of compounds which havebeen shown to be genotoxic—and may even be carcinogenic. Hexane andother petroleum-based solvents have a high E° value and good solventactivity, but they must be completely removed from the end product andalso carry with them risk of fire and explosion.

[0012] Extraction with supercritical fluid CO₂ has been used to removeactive constituents from foods such as caffeine from coffee beans, andhumulene and other flavours from hops (Humulus lupulus). The processallows for manipulation of E° value by variation of pressure,temperature and by the addition of accessory solvents (modifiers) suchas alcohols.

[0013] A characteristic of all non-aqueous solvent methods of extractionis that they all, to a greater or lesser degree, remove lipid solubleinactive material or ballast from plant material. The ballast mayconsist of plant cell constituents including but not limited to fats,waxes, carbohydrates, proteins and sugars. The presence of thesesubstances results in botanical extracts which may be hygroscopic,difficult to reduce to a powder and generally intractable as startingmaterials for pharmaceutical preparations. The presence of ballast mayalso limit the shelf-life of pharmaceutical products formulated fromsuch extracts.

[0014] Some elements of ballast can be removed by an additional steppost-extraction referred to as “winterisation”, which involves making aconcentrated solution of the extract and cooling it to a temperature atwhich a proportion of waxes and lipid components may be precipitated,typically −20° C.

[0015] Partially purified plant extracts may be further purified bychromatographic separation. High performance liquid chromatography(HPLC) is an excellent analytical technique for determination and assayof constituents and can be used in preparative mode to produce pilotquantities of concentrated fractions and individual components, providedthat the required reference standards are available. However, HPLC issubject to limitations of scale as a production technique and thereremains a need for alternative methods of separation which can be usedto produce production-scale quantities of plant extracts of sufficientquality for formulation into pharmaceutical dosage forms.

[0016] Distillation and sublimation have been used to separatecomponents of plant medicines which have boiling points at or around thetemperature at which water boils at atmospheric pressure (100° C.).Separation by distillation is a physical process widely used in thepreparation of essential oils.

[0017] GB 635,121 describes a process for the preparation of extractsfrom aromatic plants by distillation with the help of a hot gas,preferably under high vacuum.

[0018] WO 99/11311 describes a vaporizer for inhalation and a method forthe extraction of active ingredients from a crude natural product. Thismethod utilizes an ascending stream of hot air, or a heated inert gasstream, to volatilize components from the natural product. The resultantvapour may then be inhaled by a user, for example to provide therapeuticbenefit.

[0019] The present inventors have now determined that useful separationof certain plant constituents, which are not considered to be volatileat ambient temperatures, can be effected by extraction with a gas heatedto higher temperatures than those traditionally used in distillation.Accordingly, they have developed a process for the preparation ofextracts from natural products which avoids many of the disadvantages ofthe prior art and provides additional technical advantages, particularlyin the extraction of pharmacologically active components from plantmaterial.

SUMMARY OF THE INVENTION

[0020] In accordance with a first aspect of the invention there isprovided a process for preparing an extract from a natural product whichcomprises contacting the natural product with a heated gas at atemperature which is greater than 100° C. and sufficient to volatiliseone or more constituents of the natural product but does not causepyrolysis of the natural product thereby volatising one or moreconstituents of the natural product to form a vapour, and condensing thevapour to form an extract.

[0021] In accordance with a second aspect of the invention there isprovided a process for preparing an extract from a natural product whichcomprises:

[0022] providing a primary solvent extract of the natural product;

[0023] contacting the primary solvent extract with a heated gas therebyvolatilising one or more constituents of the primary solvent extract toform a vapour;

[0024] condensing the vapour; and

[0025] collecting the condensate in one or more fractions.

[0026] According to a further aspect of the invention there is providedan apparatus for extracting useful substances from natural products, theapparatus comprising a receptacle for receiving the natural product, ablower to blow gas through the receptacle, a heater for heating the gasblown through the receptacle, a condenser to condense the vapour fromthe receptacle, and a means for collecting the useful substances in thecondensed liquid.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The invention will be further understood with reference to thedrawings, in which:

[0028]FIG. 1 is a schematic diagram of a first apparatus in accordancewith the present invention;

[0029]FIG. 2 is a cross-section through the rotatable drum of FIG. 1;

[0030]FIG. 3 is a section through the drum in a plane perpendicular tothe axis of rotation;

[0031]FIG. 4 is a schematic diagram of a second apparatus; and

[0032]FIG. 4A shows the detail of a basket used in FIG. 4.

[0033]FIG. 5 is a schematic diagram of an apparatus suitable forcarrying out the solvent extract purification process of the invention.

[0034] FIGS. 6-10 are gas chromatogram traces showing the c position offractions volatilized and condensed from cannabis botanical raw materialat various temperatures, in comparison with the starting raw materialand spent herb.

DETAILED DESCRIPTION OF THE INVENTION

[0035] The process according to the first aspect of the inventioncombines a distillation step in which the natural product is contactedwith a hot gas, resulting in volatilisation of one or more constituentsof the product to form a vapour, with a condensation step in which thevapour is condensed to form an extract.

[0036] If required, the process may further include a step of removingparticulate matter from the vapour prior to the condensation step.

[0037] The process exhibits unexpected efficiency and selectivity ascompared to prior art methods of solvent extraction, particularly inrelation to the isolation of cannabinoid-rich fractions from cannabisplant material (as illustrated in the accompanying examples).

[0038] Contact between the natural product and the heated gas isadvantageously achieved by “gas washing” the product. This involvescontinuous agitation of the product in a stream of the heated gas.

[0039] The process may be operated continuously and as such isparticularly suitable for use in large scale commercial production ofextracts from natural products.

[0040] As illustrated in the accompanying Examples, the process of theinvention can produce extracts containing minimal ballast which aresuitable for direct formulation into standard pharmaceutical dosageforms, i.e. tablets, capsules, sprays, liquid formulations etc.

[0041] The condensed extract may be a homogeneous liquid but may,depending on the nature of the starting material, form a mixture of oilyand aqueous components. In the latter case, the apparatus used forcarrying out the process may include further means for separating theextract into fractions by passing vapour into a condenser with afractionating column. This type of condenser is commercially availableand contains baffle plates or other packing and multiple collectionports for separation of fractions having different boiling points.

[0042] The extraction process of the invention is particularly preferredfor preparing extracts from plant material. The term “plant material”encompasses whole plants and also parts thereof which contain theprincipal medically active constituents, for example the aerial parts ofthe plant or isolated leaves, stems, flowering heads, fruits or roots.The extraction process may be carried out starting from freshlyharvested plant material, plant material which has previously been driedby removal of water or plant material which has been subjected to someother pre-treatment step, for example to effect a chemical change inconstituents of the plant material.

[0043] When using freshly harvested plant material, for example plantmaterial which is still green, the process may advantageously include apre-treatment step in which the plant material is contacted with astream of heated gas at a temperature which is sufficient to dry theplant material, by removal of water vapour therefrom. After this initialpre-treatment step the temperature of the heated gas may be increased toa temperature which permits volatilisation of constituents of the plantmaterial.

[0044] The precise temperature of the gas used to volatiliseconstituents of the natural product may vary dependent on the nature ofthe natural product and on the nature of the constituents it is desiredto extract using the process. However, the temperature is always beabove 100° C. (during at least a part of the extraction process) and isselected not to cause substantial pyrolysis of the natural product.Typical temperatures will be in the range of from 150 to 450° C. Theextraction is preferably carried out at or above atmospheric pressure.

[0045] The temperature may be varied over the course of the extractionprocess. In one embodiment a profile of two or more discretetemperatures may be used, at least one of which is above 100° C. andselected not to cause substantial pyrolysis of the natural product. Mostpreferably the temperature of the heated gas will be increased at eachof the discrete steps. In a further embodiment the temperature of theheated gas could be continuously increased or ramped. The use of heatedgas at two or more discrete temperatures may enable components of thenatural products to be volatilised and condensed as separate fractions.

[0046] Suitable “heated gases” for use in the process include hot air.However, the use of hot air can result in oxidative degradation ofconstituents of the extract produced during the extraction process. Thisproblem can be avoided with the use of a “non-oxidising gas”. By theterm “non-oxidising gas” is meant a gas which causes less oxidation ofthe extract produced from the natural product than air under equivalentprocess conditions. A preferred type of “non-oxidising” gas is dry steami.e. steam at a temperature above 100° C. which is free of condensedwater vapour.

[0047] Further protection against the effects of oxidation can beachieved with the use of a “reducing gas”. Suitable reducing gasesinclude gases containing a pharmaceutically acceptable anti-oxidant,sulphur dioxide mixed with steam, carbon dioxide and inert gases suchas, for example, nitrogen, helium and argon. The use of a reducing gasis particularly advantageous in relation to the extraction ofcannabinoid-rich fractions from cannabis plant material, as discussedbelow.

[0048] In one particular embodiment, useful for preparation of extractsfrom freshly harvested or “wet” plant material, a reducing gas may beproduced in situ by addition of a solution of sodium metabisulphite to astream of heated steam. When mixed with wet plant material, sodiummetabisulphite reacts to produce sulphur dioxide which provides anantioxidant environment, minimising the extent of oxidation of theextract. The quantity of sodium metabisulphite added to the steam istypically sufficient to give 10-500 parts of sulphur dioxide per millionparts of wet plant material.

[0049] Surprisingly, it has been found that application of temperaturesgreater than those used for steam distillation can also speed theconversion of inactive constituents of natural products into compoundswhich are biologically active and can be separated in high purity byheating and condensation under defined conditions. For example, theprincipal active constituents of Cannabis saliva and Cannabis indica arethe cannabinoids—principally tetrahydrocannabinol (THC) and cannabidiol(CBD). Cannabinoids such as cannabigerol (CBG), cannabichromene (CHC)and other cannabinoids are present in small quantities in harvestedcannabis plants. The majority of cannabinoids are present in the plantas the corresponding carboxylic acids. The carboxylic acids themselveshave little or no biological activity and in the production ofcannabinoids for medicinal use it is necessary to convert thecannabinoid acids into free cannabinoids before extracting with solventsor other procedures. Thus when preparing extracts of cannabis byextraction with ethanol or supercritical CO₂ it is necessary to preheatthe cannabis in order to decarboxylate the cannabinoid acids to freecannabinoids.

[0050] Surprisingly, it has been found that by contacting cannabisbiomass with gas at a temperature of 105-450° C., and particularly inthe range 105-225° C., for a suitable period of time, the carboxylicacids are converted into free cannabinoids which are vaporised, and canbe condensed. The process of the invention can therefore avoid the needfor a separate decarboxylation step, since extraction of cannabis withheated gas at a temperature of 105-450° C., and preferably in the range105-225° C., results in decarboxylation and vaporisation of the activecannabinoids in a single step. The process of the invention isparticularly advantageous for preparing extracts of cannabis for thisreason. The rate of decarboxylation is a product of temperature andtime. At 145° C. 95% of cannabinoid acid is decarboxylated inapproximately 30 minutes. Lower temperatures may require a longerincubation time and higher temperatures a shorter incubation time toachieve the same degree of decarboxylation. Again this process ispreferably carried out at or above atmospheric pressure.

[0051] Preferred temperatures and times to achieve optimumdecarboxylation may vary according to nature of the cannabinoids whichit is desired to extract from the cannabis plant material. Chemovars ofcannabis have been produced which express a high proportion(typically >80% and more preferably >90%) of their total cannabinoidcontent as either THC or CBD. For convenience, these chemovars arereferred to as the “high THC” and “high CBD” chemovars, respectively. Inthe case of “high CBD” plants, preferred time/temperature profiles toachieve complete decarboxylation are 120° C. for 1 hour or 140° C. for30 mins. For “high THC” plants it is preferred to use a lowertemperature in order to avoid thermal oxidation of Δ⁹-THC to CBN andthermal isomerisation of Δ⁹-THC to Δ⁸-THC. Therefore preferredtime/temperature profiles are 105° C. for 1-2 hours or 120° C. for 30-60mins. For both high CBD and high THC chemovars higher temperatures maybe used in order to prepare extracts which are substantially free ofvolatile ballast components, for example terpenes, as discussed below.

[0052] A further surprising advantage of the process of the invention inrelation to the isolation of cannabinoid-rich fractions from cannabisplants is that the condensate so produced contains the free cannabinoidsin a high degree of purity, substantially free from waxes, sterols andother lipid-soluble components which characterise solvent extracts.Table 1 shows the percentage purity of the extract which is producedwith the equipment described in the attached diagrams, according to theprocess described in the accompanying examples. For comparison purposesTable 1 also shows the content of free cannabinoid and the correspondingcarboxylic acids in extracts produced by alcoholic extraction andextraction with supercritical carbon dioxide. The table also shows thepercentage of ballast which is extracted by these methods. It can beseen that the extraction process of the invention results in an extractwhich is substantially free of ballast. This extract is of sufficientquality to be processed directly into pharmaceutical dosage forms. Incontrast, cannabis extracts prepared by extraction with ethanol orsupercritical CO₂ contain a large proportion of ballast. For example,whilst CO₂ extraction is relatively selective, typically yielding anextract with a cannabinoid content of approximately 70% w/w, a range ofnon-cannabinoid ballast is also present. The process of the inventionexhibits markedly increased selectivity for extraction of cannabinoids.

[0053] Most of the ballast present in cannabis plant material isinvolatile material. The process of the invention is efficient inseparating the desired active cannabinoids from this involatile ballast,since the vast majority of this involatile ballast is simply notvolatilized during the hot gas extraction procedure. Thus, removal ofwaxy ballast material may be unnecessary, or at least rendered easierthan with a solvent extract. The other major ballast component is avolatile terpene-rich fraction. An unknown component of thisterpene-rich fraction is suspected to be the cause of stability problemsin solvent extracts of cannabis plant material prepared usingsupercritical CO₂ extraction. Hence, it is highly desirable to removethe volatile terpene-rich fraction.

[0054] Using the process of the invention it is possible to collect acannabinoid-rich fraction which is substantially free of volatileterpenes and wherein the majority of the cannabinoids are present in thedecarboxylated neutral form using a single-step temperature profile.This has obvious advantages in comparison to, for example, extractionwith CO₂ or ethanol in that there is no need for a separatedecarboxylation step prior to extraction or for a separate“winterisation” step to remove ballast. Furthermore, the extract issubstantially free of volatile terpenes which may cause stabilityproblems. As illustrated in the accompanying examples, for “high CBD”material a single temperature step in the range of 175-200° C. mayresult in the isolation of a cannabinoid-rich fraction which issubstantially free of terpenes. At these temperatures terpenes arevolatilised along with the cannabinoid-rich fraction but are notcondensed, and are thus lost from the system. In the case of “high THC”material it is preferred to use a lower temperature in order to avoidthermal oxidation of Δ⁹-THC to CBN or thermal isomerisation of Δ⁹-THC toΔ⁸-THC. Temperatures in the range 130-175° C. are preferred. The skilledreader will, however, appreciate that the optimum temperature may varydepending on the characteristics of the apparatus used to carry out theprocess, for example the amount of raw material processed in eachcharge, time of contact with the extracting gas and also the conditionsused for condensation of the volatilised components. Thus, for any givensystem conditions of extraction temperature and time should be optimisedempirically.

[0055] The terpene-rich fraction isolated from cannabis raw material mayitself have a commercial value as a “waste” product. Hence, it may beadvantageous to split the volatile components into terpene-rich andcannabinoid-rich fractions which are condensed and collected separately.This may be achieved by use of a multi-step temperature profile, usingat least two discrete temperatures. Since the terpene-rich fraction ismore volatile than the cannabinoid-rich fraction it can be removed in aninitial extraction step at a lower temperature. The temperature may thenbe increased in order to volatilise the cannabinoid-rich fraction. Thetemperature required to preferentially volatilise terpenes may varydepending on the nature of the starting cannabis plant material, but canbe readily determined by experiment as would be apparent to one skilledin the art. By way of example, for “high CBD” material a temperature inthe range 125-150° C. is observed to result in preferentialvolatilization of a terpene-rich fraction. Whereas, for “high THC”material a temperature in the range 60-90° C. is required. In order tooptimise condensation of the volatile terpene fraction the conditionsused for condensation may also be varied, in addition to the temperatureof the heated gas used to volatilize this component.

[0056] Once the terpene-rich fraction has been removed, the temperatureof the hot gas may be increased in order to volatilise thecannabinoid-rich fraction. Again, the optimum temperature for extractionof the desired cannabinoid components may be determined by experiment.By way of example, for “high CBD” cannabis plants a temperature in therange 175-200° C. is preferred. Whereas, for “high THC” cannabis plantsa temperature in the range 130-175° C. may be suitable. At 200° C. acannabinoid-rich fraction may still be collected but thermal degradationof Δ⁹-THC is increased. Hence it is preferred to use a lowertemperature.

[0057] Thus, the skilled reader will appreciate that by simple empiricalvariation of the conditions used for volatilisation and condensation itis possible to optimise separation of the terpene-rich andcannabinoid-rich fractions.

[0058] A still further advantage of the process of the invention inrelation to the preparation of cannabinoid-rich fractions from cannabisplants is that the extracts prepared using the process containcannabinoid components in approximately the same ratio as present in thestarting material. Thus, substantially no fractionation of thecannabinoids is observed.

[0059] In the context of this application the terms “cannabis”,“cannabis plant material” or “cannabis biomass” refer to whole cannabisplants and also parts thereof which contain the principal medicallyactive constituents, for example the aerial parts of the plant orisolated leaves and/or flowering heads. The terms “cannabis” and“cannabis biomass” encompass freshly harvested plant material, and alsoplant material which has been subjected to a pre-treatment step such as,for example, material which has been dried. This includes cannabismaterial which has been allowed to air dry after harvesting.

[0060] It is convenient to process high CBD and high THC cannabischemovars separately to produce extracts rich in either THC or CBD fromwhich mixtures containing defined proportions of THC and CBD can be madein the preparation of pharmaceutical formulations. Procedures describedin the following examples with reference to one particular chemovar maybe applied mutatis mutandis for any other cannabis chemovar.

[0061] In a further embodiment of the invention the principle ofextraction with a heated gas may be utilised in a two-stage process forthe preparation of extracts from plant materials which involves firstpreparing a primary solvent extract from the plant material.

[0062] As discussed previously, it is known to make an extract fromplant material by percolation or maceration with a solvent and tofractionate the extract by concentration or various processes which havebeen described in the scientific literature for reducing extracts to apowder. However, botanical extracts prepared using such processesgenerally contain a variable, but usually considerable, proportion ofinactive material or ballast which renders the extracts generallyintractable as starting materials for pharmaceutical preparations.

[0063] The inventors have now observed that primary solvent extracts ofnatural products, such as plant material, may be further purified byextraction with a heated gas, resulting in removal of a substantialproportion of the inactive ballast.

[0064] Therefore, in accordance with a second aspect of the inventionthere is provided a process for preparing an extract from a naturalproduct which comprises:

[0065] providing a primary solvent extract of the natural product;

[0066] contacting the primary solvent extract with a heated gas therebyvolatilising one or more constituents of the primary solvent extract toform a vapour;

[0067] condensing the vapour; and

[0068] collecting the condensate in one or more fractions.

[0069] This process (referred to hereinafter as the “solvent extractpurification” process) may be used to prepare a “purified” extractstarting from a primary extract of a plant material. The term “purifiedextract” refers to an extract which retains one or more desirableconstituents from the starting primary extract but contains a loweramount of other, undesirable constituents. In a preferred embodiment thesolvent extract purification process may be used to prepare a purifiedextract which retains pharmacologically active constituents from theprimary extract whilst removing unwanted ballast.

[0070] The primary extract used as the starting material for the solventextract purification process may be essentially any solvent extract of aplant material such as, for example, cannabis plant material. Extractsprepared with alcohols such as, for example, ethanol, methanol,isopropanol or industrial methylated spirit are particular suitable.Another suitable solvent is acetone. Extracts prepared by extractionwith supercritical CO₂ may also be used.

[0071] Solvent extracts prepared with alcohols may be dried down byevaporation of the solvent to yield a soft extract (as defined in theBritish Pharmacopoeia) and then re-dissolved in the same or a differentsolvent prior to contact with the heated gas. This will allow foradjustment of the concentration and viscosity of the extract prior tocontact with the heated gas. The term “primary solvent extract” as usedherein is therefore to be construed as encompassing extracts which havebeen dried down and re-dissolved.

[0072] In the case of cannabis, it is preferred to use a primary extractprepared using a mixture of alcohol and water. The use of such mixturesreduces the lipophilicity of the solvent system and leads toproportionately greater extraction of cannabinoid acids. The extractionof cannabinoid acids in progressively more dilute alcohols is observedto be increased at high pH.

[0073] The primary solvent extract may be prepared using conventionaltechniques known in the art such as, for example, maceration,percolation and reflux (Soxhlet) extraction. The solvent used forprimary extraction may be chosen according to the known solubilitycharacteristics of the active ingredients or their precursors in theplant material. Since it will be subject to a further extraction stepthe primary solvent extract may be a fairly crude extract.

[0074] In a preferred embodiment the step of contacting the contactingthe primary solvent extract with a heated gas comprises loading theprimary solvent extract onto a matrix of inert, porous material andcirculating a heated gas through the matrix, thereby volatilising one ormore constituents of the primary solvent extract to form a vapour.

[0075] The primary solvent extract is loaded onto a matrix of inert,porous material which provides a large surface area for contact betweenthe primary extract and the heated gas. Suitable inert matrix materialsinclude glass wool, which may be coated (e.g. silanised) to modify itssurface retentiveness. In one embodiment the glass wool may be in theform of a pre-formed mat of spun glass (Rockwool), rolled to form acylinder. Other suitable inert, porous matrix materials include, forexample, glass beads or short sections of glass tube, borosilicate glassor pharmaceutical grade stainless steel. For convenience, the matrixmaterial maybe packed into a column formed of an inert material, such asborosilicate glass. A suitable apparatus is described below andillustrated in the accompanying examples.

[0076] Heated gas is then circulated through the matrix material inorder to volatilise one or more constituents of the primary solventextract, forming a vapour. The temperature of the heated gas will varydepending on the nature of the component(s) which it is desired tovolatilise from the primary extract. The temperature of the heated gasmay also be varied over time. For example, depending on the compositionof the primary extract it may be desirable to circulate heated gas at afirst temperature in order to volatilise unwanted components of theprimary extract and then to adjust the temperature to a second, highertemperature to volatilise desirable components of the primary extract.

[0077] Suitable “heated gases” for use in the process include hot air,inert gas and dry steam, alone or in combination. The most preferredgases are inert gases, dry steam and mixtures thereof. Mixtures of inertgas and dry steam are referred to as anaerobic gas mixtures. Byexcluding air, through use of an anaerobic gas mixture, oxidativedegradation of the extract is reduced or avoided. Examples of suitableanaerobic gas mixtures are dry steam mixed with one or more of nitrogen,carbon dioxide, helium or argon.

[0078] Oxidation can be further reduced by use of a reducing gasmixture. By “reducing gas mixture” is meant an anaerobic gas mixturecontaining a proportion of a volatile antioxidant, or means forgenerating an antioxidant in situ during the extraction process.

[0079] The vapour produced by volatilisation of constituents of theprimary solvent extract is condensed and collected. The condensate maybe a homogeneous liquid but may, depending on the nature of the startingmaterial, form a mixture of oily and aqueous components. In the lattercase, the apparatus used for carrying out the process may furtherinclude means for collecting the condensate in two or more separatefractions.

[0080] The primary solvent extract may be subjected to a chemicaltreatment prior to loading onto the inert matrix. In one embodiment, theextract may be treated to adjust pH, for example by addition of an acidor an alkali. Where the active constituent which it is desired toisolate from the plant material is an alkaloid salt or other adduct, thealkaloid may be rendered volatile by adjustment of pH. Subsequenttreatment with heated gas at a temperature which volatilises thealkaloid may then result in a product which is substantially free ofinactive ballast.

[0081] Surprisingly, it has been found that use of the solvent extractpurification process can speed the conversion of inactive constituentsof plant materials into compounds which are biologically active and canbe separated in high purity. For example, as described above thecannabinoids which are the principal active constituents of cannabisplants, particularly Cannabis saliva and Cannabis indica, are present inthe plant as the corresponding carboxylic acids. With use of the solventextract purification process it is possible to prepare a purifiedcannabis extract, containing a high proportion of free cannabinoids,starting from a primary solvent extract. There is no need to perform aseparate decarboxylation step before preparation of the primary solventextract. A primary extract is simply prepared from cannabis plantmaterial, loaded onto matrix material and treated with heated gas.Circulation of the heated gas through the primary solvent extractresults in decarboxylation of cannabinoid acids and volatilisation offree cannabinoids in a single process step. The vapour comprising thefree cannabinoids is collected by condensation. The resulting condensateis substantially free of inactive ballast and suitable for formulationinto pharmaceutical dosage forms.

[0082] The temperature of the heated gas used in the processing ofcannabis extract must be sufficient both to effect decarboxylation ofcannabinoid acids and to volatilise the free cannabinoids. Temperaturesin the range of 105°-350° C., and preferably 125°-218° C. are suitablefor this purpose. Decarboxylation of cannabinoid acids is a function oftime and temperature, thus at lower temperatures a longer period of timewill be taken for complete decarboxylation of a given amount ofcannabinoid acid.

[0083] According to a further aspect of the invention there is providedan apparatus for extracting useful substances from natural products, theapparatus comprising a receptacle for receiving the natural product, ablower to blow gas through the receptacle, a heater for heating the gasblown through the receptacle, a condenser to condense the vapour fromthe receptacle, and a means for collecting the useful substances in thecondensed liquid.

[0084] In one embodiment, the receptacle is a drum rotatably mounted ina housing to rotate about an axis. Alternatively, the receptaclecomprises a stack of baskets each having a perforated base which allowthe passage of gas, but substantially not the natural product.

[0085] Examples of apparatus according to the invention will now bedescribed with reference to FIGS. 1 to 4.

[0086] The primary component of the apparatus shown in FIGS. 1 to 3 is arotatable drum 1 which is mounted in a housing 2. The drum 1 is mountedfor rotation about an axis 3. The drum 1 has an octagonal cross-sectionin a plane perpendicular to the axis 3 as shown in FIG. 3. Each side ofthe drum 1 comprises a mesh sheet 4 having a wire diameter of 0.16 to0.28 mm and an open area of 45 to 39% which is designed to retainparticles of 1×2 mm. The front of the drum is closed by a plate 4Abolted in place and held by a plurality of wing nuts 4B.

[0087] The drum 1 is driven by a variable speed geared motor 5 coupledvia torque coupling 6 to a rotatable shaft 7 supported on a pair ofbearings 8. The rotatable shaft 7 enters the housing 2 through a lipseal 9 and has a key groove 10 which engages with a complementary keyrib in the drum so as to transmit rotational movement thereto. A drainpart 2A is provided in the bottom of the housing 2 to allow anyaccumulated liquid in the housing to be drained.

[0088] The housing 2 is open at the end opposite to the motor 5. Thisopening is selectively closable by a hinged door 11 and seals by virtueof an annular seal 12. The door 11 is provided with an inspection window13 as shown in FIG. 1. The loading and unloading of the product isaccomplished by removing the wing nuts 4B and hence plate 4A, removingany spent product, replacing it with fresh product and replacing theplate 4A and wing nuts 4B. To clear the equipment between batches, theentire drum 4 may be removed from the housing 2, by unfastening the drumfrom the shaft 7. The drum 4 can then be cleaned and reused. It will bequicker, however, to have a second drum which is pre-filled with productand can be used in place of the first drum while the first drum iscleaned.

[0089] Hot gas is blown into the housing 2 through an air knife 14supplied from hot gas supply nozzle 15. The air knife 14 provides a longthin air duct extending parallel to axis 3 for substantially the entirelength of the drum 1. The air knife 14 is positioned immediatelyadjacent to the drum 1, and is directed generally towards the centre ofthe drum, but not directly at the axis 13.

[0090] In use, a natural product such as medicinal cannabis is coarselychopped and loaded into the drum 1 as described above. The cannabis maybe in its “as grown” state, or may have been subjected to apre-treatment step, for example a drying step. Typically 5 kg ofcannabis will be loaded into the drum. A gas such as nitrogen isinjected through a duct 20 and is blown by a sealed fan 21 through aheater 22, where it is heated to a temperature of around 200° C., viahot gas supply duct 15 and into the housing 2 through the air knife 14.Simultaneously with the gas injection, the drum 1 is rotated by themotor 5 at a rate of between 0.1 and 60 r.p.m. This rotary motion causesthe product to fall through the space in the drum, while the hot gasflowing through the air knife 14 keeps the product away from the wallsof the drum. The hot gas causes the active substances within the productto vaporise and the hot vapour leaves the housing 2 through an outlet16. A filter 17 traps large particles entrained in the vapour.

[0091] The vapour then travels along discharge duct 23 to a cycloneseparator 24 which separates out smaller particles from the vapour. Itis possible that either the filter 17 or the cyclone separator 24 willbe sufficient on its own to separate out all of the particulates fromthe vapour.

[0092] The vapour which is now substantially free of solids leaves thecyclone separator 24 through cyclone outlet duct 25 and passes throughthe fan 21. Temperature can be equilibrated and vapour can berecirculated by closure of motorised butterfly valves 26 and 26A. Vapourpasses through a condenser 28. The condenser 28 is cooled by a waterjacket 29 to which water is supplied through duct 30 and returnedthrough duct 31. The distillate leaving the condenser 28 containing theactive substance accumulates in collector 32. The vapour may be ventedvia a steam trap 33 or may be recirculated via a scrubber 34 or an icedchiller 35 along return line 36 where it joins the recirculating hot gasstream upstream of the heater 22. The scrubber 34 may be a glass wool orcharcoal scrubber and is designed to remove the smell from the vapour. Apreferred type of scrubber contains C18 reverse-phase chromatographysupport in granular, permeable form which effectively absorbs anyparticles of lipid-soluble material. The chiller 35 is provided to chillthe vapour to condense terpenes. A typical design of chiller utilises afreezing mixture of acetone and solid carbon dioxide giving atemperature of −65-70° C. to condense remaining traces of vapour.

[0093] Prior to use, and before any natural product is placed in thedrum, the apparatus is flushed with nitrogen which is then ventedthrough vent 36 prior to heating.

[0094] A dry steam inlet 38 may also be provided to give an anaerobicalternative to nitrogen. Dry steam allows vaporisation to occur at alower temperature than with nitrogen.

[0095] In practice, the apparatus upstream of the condenser (i.e. thehousing 1, heater 22 and cyclone 23) will be housed in a commoninsulated container to avoid expensive lagging of individual components.

[0096] An alternative apparatus is shown in FIG. 4. As with the examplein FIG. 1, the apparatus in FIG. 4 is also designed to force a stream ofheated gas through a perforated container holding a supply of naturalproducts such as medicinal cannabis.

[0097] The apparatus of FIG. 4 comprises a sealed and insulated housing40 into which gas flows through a heated gas inlet 41. This inlet 41passes through a heat exchanger 42 such that the cold incoming gas isheated with hot outgoing gas as will be described below. The interior ofthe housing 4 is heated by an electric heater 43 such that the preheatedgas entering the housing 40 is heated further. A fan (not shown) isprovided to drive the air into the housing 40. A double acting pump 44is positioned within the housing 40. This consists of a piston 45 whichreciprocates within a cylinder 46. The pump has a first inlet valve 47which allows air into the top of the cylinder during the pistondownstroke and a second inlet 48 which allows air into the bottom of thecylinder during the piston upstroke. A first outlet 49 lets air out ofthe top of the cylinder during the piston upstroke while a second outlet50 allows air out of the cylinder during piston downstroke. Flow througheach of the inlet and outlet valves is controlled by a one-way flapvalve. Thus, the double acting pump 44 provides a cyclic varying outputof hot gas which is conveyed via a duct to a carousel assembly 51.

[0098] The carousel assembly 51 comprises an upper disk 52 and anaxially aligned lower disk 53, both of which are connected to a spindle54 which passes through their centres. The spindle is rotatable so as torotate the upper 52 and lower 53 disks. Each of the upper 52 and lower53 disks passes through the wall of the housing 40 and a seal 55 isprovided at each interface. Each disk 52, 53 is provided with a number,preferably two or more and typically six, of circular orifices 56, eachof which is sized to receive a basket 57. Baskets 57 have a mesh base57A and solid walls 57B with a recess in the rim to retain a siliconerubber ring washer 65. The baskets nest together and the ring washerensures that gas passes through the baskets and their content and notaround them. The baskets 57 are loaded by upper disk 52 into a column58. The first loaded basket drops down the column 58 and is supportedabove a series of baffles 59 at the lower end of the column 58. Furtherbaskets 57 are then loaded on top of this.

[0099] Initially, a full stack of baskets is inserted as shown. Thedouble acting pump 44 is then operated to push hot gas upwardly throughthe column. Gas expelled from the top of the column passes through heatexchangers to pre-heat the incoming gas. The flow of hot gas up column58 vaporises the active ingredient as in the previous example, and theexpelled vapour is treated as previously described with reference toFIG. 1, namely be being passed through a separator such as a filter orcyclonic separator into a condenser 60. Also shown in this example is anoptional secondary condenser 61 and exhaust pump 62. The condenser 60has an upper outlet 63 and lower outlet 64 to allow withdrawal ofdifferent fractions of the condensate should it separate into layers.Such an arrangement may also be employed with the condenser of FIG. 1.

[0100] As the process progresses, the product in the lowermost basket 57will be exhausted at a faster rate than the product in successivelyhigher baskets because it encounters the freshest gas, i.e. a countercurrent flow arrangement is operated. After a certain time, or once thelevel of active substances being collected has dropped below a certainlevel, the lowermost basket is removed by rotation of the lower disk 53which takes the basket outside the housing 40 where it can be removedfor disposal. A fresh basket is pre-loaded into an orifice 56 in theuppermost basket 52 outside the housing 40. As the lowermost basket isremoved, the upper disk is rotated bringing the fresh basket into alocation at the top of the column 58. A reciprocable plunger 66 is thendeployed to push the new basket out of the hole 56 in the upper disk 52and to ensure that all of the baskets 57 are pushed down the column 58so that the lowermost basket rests on the baffles 59.

[0101] After a suitable interval, this process is repeated so that freshbaskets of product are periodically added to the top of the column andgradually progress down the column until they are removed from thebottom.

[0102]FIG. 5. shows a small scale laboratory apparatus suitable forcarrying out the solvent extract purification extraction process. Thisapparatus may be assembled from commercially available proprietarylaboratory glassware. The apparatus comprises a hollow cylindricalcolumn 69 formed of borosilicate glass or similar inert material. Thecolumn is packed with an inert matrix material 70, for example glasswool, glass beads or short sections of glass tube. A heating mantle 71is fitted around cylindrical column 69 and provides heat and insulationto maintain the cylinder at its operating temperature. In otherembodiments the column may be contained within an oven which ismaintained at a specific temperature controlled by a thermostat.

[0103] The apparatus further includes a re-circulation pipe 72 fittedwith a valve 73 and sampling port 74 and a outlet pipe 75 also fittedwith a valve 76 which feeds into the condenser assembly. The condenserassembly of the apparatus shown in FIG. 5. includes two condensers 77,78arranged in series.

[0104] Heated gas is introduced into the device via an inlet port 79 atthe bottom of the cylindrical column. A stream of heated gas may beconveniently provided using an electrical heater/blower device.

[0105] The re-circulation pipe 72 operates to re-circulate gases thoughthe column when valve 73 is in the open position and valve 76 is in theclosed position. When valve 73 is closed and valve 76 is open gases exitthe cylinder via outlet pipe 75 and are delivered to the condenserassembly. Condensate exiting the condenser assembly is collected in areceiving vessel (not shown).

[0106] The apparatus further includes a thermistor 80 and flow gauge 81for monitoring the temperature and flow of gas in the apparatus.

[0107] The invention will be further understood with reference to thefollowing, non-limiting, experimental examples.

EXAMPLE 1 Extraction with Ethanol

[0108] The following method of extraction is essentially that describedin major pharmacopoeias such as the British Pharmacopoeia, EuropeanPharmacopoeia and United States Pharmacopoeia. It is included here toprovide a datum point for comparison of the extracts produced by methodsillustrated in later examples. The method can be used mutatis mutandisto prepare total extracts of other chemovars of cannabis.

[0109] High Δ⁸-tetrahydrocannabinol (THC) cannabis chemovar, coarselychopped in a cutter mill, is decarboxylated by heating at 145° C. forone hour. A quantity of 100 g of decarboxylated herb is packed into acylindrical vessel fitted with a frit (mesh screen) to retain solidparticles and a tap in the exit tube. A second frit is placed overchopped cannabis to prevent splashing. The cannabis is moistened with90% ethanol; a further quantity of ethanol is added to completelysaturate the plant material and allowed to stand for 24 hours. The tapis opened and the percolate is collected. A drip feed of ethanol isfixed up above the cannabis so that the mass remains saturated withethanol. Percolation is continued, reserving the percolate until thepercolate is no longer darkly coloured, and when 1 ml of percolatetested by HPLC shows less than the equivalent of 0.1 mg of THC per ml.The presence of cannabinoid is revealed by adding 0.1 ml of Fast BlueTest Solution is added to 1 ml percolate. Cannabinoids producecharacteristic colours (orange —CBD; pink—THC; and purple —CBD) in thistest.

[0110] The reserved percolate is then evaporated to dryness in a rotaryevaporator and assayed by HPLC. Essential details of the assay methodare given below. A person skilled in the art will appreciate that otherconfigurations of column, mobile phase and operating conditions havingthe required discrimination and accuracy are suitable for the purposesof estimating cannabinoid content. Extract: Typically 0.1 g of groundplant tissue/5 ml of chloroform, methanol 1.9 g Columns: S3 ODS2 3 ×0.46 cm pre-column and Discovery C8 15 × 0.46 cm analytical columnMobile Phase: 0.25% w/v acetic acid in Water: Methanol: Acetonitrile 6:7: 16 (by volume) Flow Rate: 1 ml/min Detection: UV at 220 nm Injectionvolume: 2 μl

[0111] From Table 1 it can be seen that the extract so produced consistsof THC principally, but there is also present some of the carboxylicacid (THCA), a little CBD, some CBDA and cannabinol. The remainder ofthe extract consists of ballast. Table 1 also gives the analysis of theextract produced from the high CBD chemovar using the method describedabove and shows that there are significant amounts of ballast present inthe dry extracts. The product is a dark oleoresin; the dark brown colourindicating that there is considerable oxidation of plant pigments. Themethod can be used to produce an extract from the high CBD chemovar bysubstitution of the appropriate plant mass.

[0112] Ethanol extraction may be optimised by varying pH and/or strengthof the ethanol solvent. Surprisingly it has been found that at high pHvalues, the carboxylic acids corresponding to cannabinoids are solublein lower concentrations of ethanol/water, and that under theseconditions there is more complete extraction of total cannabinoidcontent as shown by gravimetric determination.

EXAMPLE 2 Extraction with Supercritical Carbon Dioxide

[0113] 100 g of cannabis (high CBD chemovar) are coarsely chopped in aHobart cutter mill then decarboxylated as described in Example 1. Plantmass is packed, tamping down between successive layers, into the cavityof a supercritical fluid extraction apparatus. The mass is furthercompacted by axial pressure and frits are installed at either end of thecannabis mass. Carbon dioxide at a pressure of 100 bar and a temperatureof 32° C. is admitted to the apparatus and extraction continued for 4hours. At the end of this time eluate is vented through a pressurereduction system and the extract emerging at atmospheric pressure iscollected in a glass vessel as a yellow/brown oil.

[0114] The distillate is dissolved in dehydrated ethanol and cooled to atemperature of −20° C. ±1° C. for 24 hours and the waxy material removedby filtration. This process, known as “winterisation”, is used in theoil industry to de-wax oils, but only removes a percentage of lipidmaterial in extracts of cannabis (Table 1).

[0115] From Table 1 it can be seen that the product produced by thisprocess is a yellow/brown oil which is lighter in colour than thatproduced by ethanolic extraction but the extract still containssignificant quantities of carotenoid pigments. It also containssignificant amounts of cannabinol which is regarded by some authoritiesas a degradation product of THC and CBD.

EXAMPLE 3 Extraction with Heated Gas (Nitrogen)

[0116] Five kilos of coarsely chopped medicinal cannabis was loaded intothe drum of an apparatus of the type shown in FIG. 1. Distillation ofcannabinoids was effected with the use of pharmaceutical qualitynitrogen at a temperature between 175° C. and 250° C., which is belowthe temperature at which plant material chars or pyrolyses.

EXAMPLE 4 Extraction with Heated Gas (Reducing Steam)

[0117] Using apparatus of the type illustrated in FIG. 1, 5 kg offreshly harvested cannabis was placed into the drum. The cannabisflowering heads and leaves were separated from stalk using a serratedcomb with sharpened tines. The apparatus was equilibrated to atemperature of 110° C. and steam was introduced at 150° C. while thedrum was set to rotate. A solution of sodium metabisulphite (10%) isintroduced into the flow of steam in a quantity sufficient to give10-500 parts of sulphur dioxide per million parts of wet biomass. Whenmixed with wet biomass, sodium metabisulphite reacts to produce sulphurdioxide which provides an antioxidant environment in which theextraction can be carried out. Oxidation of the extract is therebyminimised.

[0118] Vapour leaving the chamber was condensed and produced a mixtureof oil and aqueous layer. The volatile oil so produced is useful as acomponent of medicinal flavouring and perfumery products. The collectingvessel was fitted with two taps, one at the lowest point and the otherat a point on the wall of the glass container. After separation it ispossible to draw off the saturated aqueous layer which containsconsiderable amounts of terpenes and other odiferous principles; theoily cannabinoid-rich fraction is discharged through the upper tap. Bycontrolling the temperature of the condenser and the collection vesselit is possible to keep both aqueous and oily layers in non-viscous,liquid form for ease of handling.

[0119] It is apparent by observation of the oil level in the condenserwhen distillation of this fraction is substantially complete. At thispoint the contents of the condenser are removed. Steam was replaced withnitrogen and the temperature raised to 218° C. The receptacle forcondensed liquor was replaced and the temperature in the reactorincreased to 218° C. The vapour now produced was condensed andcollected, as follows.

[0120] The vapour is admitted to a condenser which is cooled with waterat a temperature of 50° C. Condensed material is still fluid at thistemperature and may be collected in a suitable receptacle.

[0121] Vapour leaving the condenser may be passed through a cold fingerchilled with carbon dioxide and acetone coolant which condenses valuablecomponents remaining in the vapour. TABLE 1 Characteristics of Extractof Cannabis Method of Ballast (after Extraction Chemovar Appearance ofExtract THC THCA CBD CBDA CBN Winterisation 90% ethanol G1 Dark brown 504 1 2 2 40 (Example 1 90% ethanol G5 Dark green/brown 3 0.5 55 5 2 34(Example 1) SCCO₂ G1 Yellow/green/brown 60 6 1.5 2.5 2 ( ) (Example 2)oleoresin SCCO₂ G5 Yellow/Green/brown 4 0.5 54 4 2 ( ) (Example 2)Distilled G1 Light Yellow 98 trace 2.5 trace 0.5 trace (Example 4)Distilled G5 Light yellow solid 1.5 trace 98 trace 0.5 trace (Example 4)

EXAMPLE 5 Heated as Extraction from High CBD Cannabis Chemovar

[0122] The following studies were carried out using a pilot-scaleversion of the apparatus of FIG. 1. The apparatus can be runcontinuously and accepts a charge of 50 g botanical raw material, whichis heated for approximately 15 mins.

[0123] The starting botanical raw material was a high CBD cannabischemovar (designated G5) containing more than 90% of total cannabinoidas CBD and its precursors. Extraction was carried out by contacting thebotanical raw material with forced hot air flow at various selectedtemperatures. An inert atmosphere of nitrogen could be substituted forthe flow of air, for example if it is necessary to prevent oxidation ofthe minor cannabinoid component THC to CBN. Volatilised components werecondensed by means of a “cold finger” filled with a salt/ice freezingmixture.

[0124] A series of experiments were carried out to determine thetemperature profile required to resolve the cannabinoids, consistingpredominantly of CBD, from the unwanted terpene fraction (volatile oilfraction with gas chromatogram R.T.'s in the region 14 min-21 min). Abasic approach of a lower temperature initial phase, to volatiliseterpenes and other essential oil components, followed by a highertemperature phase to volatilise the higher boiling point cannabinoidswas adopted. FIGS. 6-8, which show gas chromatography analysis of thecondensed factions collected following volatilisation at each of thechosen temperatures, plus GC analysis of starting material and spentherb. GC results obtained for the starting material (botanical rawmaterial) and spent herb after each run are based on the analysis oftotal solvent extractable fraction. This is representative of thequalitative composition of the herbal material before and after hot gasextraction.

[0125] The results obtained may be summarised as follows:

[0126] 125° C./200° C. (FIG. 6.)

[0127] The low temperature phase produces no significant volatilisationof any components (during the time period of this study). The highertemperature phase produces significant volatilisation of cannabinoidwhich is collected on the cold trap, but the volatile terpene fractionis not condensed and is lost from the system.

[0128] 150° C./200° C. (FIG. 7.)

[0129] The low temperature phase produces significant volatilisation ofboth terpene fraction and cannabinoid, both of which are collected onthe cold trap to produce a complex mixed fraction. The most abundantpeak in the terpene region of the GC trace is a new compound not presentin the starting material, which may represent an oxidised terpeneproduct. The high temperature phase results in a cannabinoid-richfraction containing little terpene.

[0130] 175° C./200° C. (FIG. 8.)

[0131] The low temperature phase produces cannabinoid enriched richfraction essentially free of terpenes. The high temperature phaseproduces a fraction of comparable composition to that obtained duringthe low temperature phase.

[0132] The employment of a two-stage temperature profile can thus resultin successful separation of cannabinoid from the terpene fraction,resulting in a cannabinoid enriched extract. Furthermore, it can bederived from these results that a single-stage temperature profile at atemperature of 175° C.-200° C. will also result in the production of acannabinoid-enriched fraction substantially free of terpenes (see FIG.6. 200° C. step, and FIG. 8).

[0133] Decarboxylation during the vaporisation process appeared to beessentially quantitative, with only neutral cannabinoid and no aciddetected in the condensed fractions. Both CBD principal cannabinoid andthe THC minor cannabinoid were present in the volatilised extract inapproximately the same ratio as detected in the herbal startingmaterial, indicating that no fractionation of cannabinoids had occurred.

[0134] Comparison of the results shown in FIGS. 6 and 7 indicates that atemperature of above 125° C. but below 150° C. is required topreferentially volatilise terpenes in this system. Optimisation of theextraction temperature within this range may allow preferentialvolatilisation of a terpene fraction which can be condensed andcollected fraction, substantially free of cannabinoids.

EXAMPLE 6 Heated Gas Extraction from High THC Cannabis Chemovar

[0135] The following studies were carried out using a pilot-scaleversion of the apparatus of FIG. 1. The apparatus can be runcontinuously and accepts a charge of 50 g botanical raw material, whichis heated for approximately 15 mins.

[0136] The starting botanical raw material was a high THC cannabischemovar (designated G1) containing more than 95% of total cannabinoidas THC and its precursors. Extraction was carried out by contacting thebotanical raw material with forced hot air flow at various selectedtemperatures. An inert atmosphere of nitrogen could be substituted forthe flow of air, for example to prevent oxidation of the cannabinoidcomponent THC to CBN. Volatilised components were condensed by means ofa “cold finger” filled with a salt/ice freezing mixture.

[0137] A series of experiments were carried out to determine thetemperature profile required to resolve the cannabinoids, consistingpredominantly of THC, from the unwanted terpene fraction (volatile oilfraction with gas chromatogram R.T.'s in the region 14 min-21 min).Special considerations in the extraction of THC are to prevent/minimisethermo-oxidative degradation of THC to CBN and to prevent/minimisethermal isomerisation of Δ⁹-THC to Δ⁸-THC, whilst avoiding collection ofterpenes with the cannabinoid fraction.

[0138] A basic approach of a lower temperature initial phase, tovolatilise terpenes and other essential oil components, followed by ahigher temperature phase to volatilise the higher boiling pointcannabinoids, optionally with the inclusion of a third intermediatetemperature phase, was adopted. FIGS. 9 and 10 show gas chromatographyanalysis of the condensed factions collected following volatilisation ateach of the chosen temperatures, plus GC analysis of starting materialand spent herb.

[0139] GC results obtained for the starting material (botanical rawmaterial) and spent herb after each run are based on the analysis oftotal solvent extractable fraction. This is representative of thequalitative composition of the herbal material before and after hot gasextraction.

[0140] The results obtained are summarised in the following table: TABLE2 SAMPLE Δ⁹-THC CBN Δ⁸-THC CBD THC:CBN BRM (G1) 75.5%  3.0%  0.3% 1.9%  28:1 Run 1 125° C. 51.5%  6.2%  0.4% 1.2%  8.3:1 200° C. 63.3% 12.8% 0.5% 1.1%  4.9:1 spent herb  3.0% 11.1% 17.2% N.D.  0.3:1 Run 2  90° C.58.0%  5.6%  0.3% 1.8% 10.4:1 150° C. 82.7%  9.6%  0.4% 1.5%  8.6:1 200°C. 77.1% 14.1%  0.7% 1.0%  5.5:1 spent herb 54.0% 25.7%  2.6% N.D. 2.1:1 Run 3  60° C. 78.6%  7.2% N.D. N.D. 10.9:1 125° C. 75.3%  6.0%N.D. 1.8% 12.6:1 200° C. 83.0% 10.2%  0.2% 1.6%  8.1:1 spent herb 64.1%23.7%  0.6% 0.9%  2.7:1

[0141] The results from run 3 indicate that a temperature of above 60°C. is required in order to volatilise terpenes. At a temperature of 90°C. (run 2) terpenes are volatilised, but only the less volatile terpenesare condensed. These results suggest that a temperature between 60° C.and 90° C. may be optimum for volatilisation and condensation of aseparate terpene fraction.

[0142] The results from run 2 indicate that at 150° C. acannabinoid-rich fraction is condensed, which is substantially free ofterpenes. A similar profile is obtained at 200° C., however at thistemperature the amount of Δ⁸-THC and CBN is increased, indicatingthermal-oxidative degradation and thermal isomerisation of Δ⁹-THC.Similar results are seen in run 3, where the fraction obtained at 200°C. is free of terpenes but contains a higher proportion of Δ⁸-THC andCBN. It is therefore preferred to use a temperature which is as low aspossible in order to minimise thermal-oxidative degradation and thermalisomerisation of Δ⁹-THC, whilst still resulting in a fraction which issubstantially free of terpenes. A range of from 130° C. to 175° C. ispreferred.

EXAMPLE 7 Purification of an Ethanol Extract by Extraction with HeatedGas

[0143] High pH and low pH ethanolic solutions were prepared by adding 5ml of m/1 sodium hydroxide or hydrochloric acid solution to absoluteethanol and sufficient purified water to produce 100 ml of solvent. Thisquantity of solvent was used to percolate 10 g of cannabis herb, asdescribed in Example 1.

[0144] Percolation of the cannabis herb was continued to exhaustion asdescribed in Example 1 and evaporated to a soft extract (as defined inthe British Pharmacopoeia). The extract was re-dissolved in ethanol togive a solution with a viscosity in the range 100-500,000 cps(preferably 50-150,000 cps using a Brookfield viscometer) and pouredonto the cylindrical column of an apparatus of the type illustrated inFIG. 5. The column was constructed of borosilicate glass and packed withglass wool. Sufficient quantity of extract was added to coat but notsaturate the column. Care was taken to ensure that the extract wasretained within the pre-packed column.

[0145] The loaded column was assembled and connected to a condenserassembly and an electrical heater/blower. Air at a temperature of 60°C.-120° C. was blown through the cylinder and maintained at the sametemperature. At this temperature volatile components consisting mainlyof water, alcohols, and low boiling point terpenes are volatilised thencondensed and collected in the receiver. When distillation of these lowboiling components was substantially complete (indicated by a rise intemperature in the vapour leaving the column), the supply of gas wasstopped and the receiver changed or emptied.

[0146] The temperature of the cylindrical column was increased to 218°C. and gas blown through the cylinder for 20 minutes. The gas wasre-circulated through the cylinder with valve 76 closed and valve 73opened. During this period cannabinoid acids are decarboxylated.Decarboxylation is substantially complete when a sample is taken fromsampling port 74 shows that the free cannabinoid has reached a maximumlevel, measured by HPLC. At this point valve 76 was opened and valve 73closed. Vapour was condensed in the condenser assembly and the condenseddistillate collected. The distillate so produced consists of the totalcannabinoids of the extract with very little cannabinoid acid, and issuitable for formulation into pharmaceutical dosage forms.

EXAMPLE 8 Preparation of a Methanolic Extract

[0147] Total extracts of high THC and high CBD cannabis chemovars wereprepared using ethanol as follows:

[0148] Biomass from each chemovar was separately extracted in a columnwith methanol at room temperature, and the pooled percolate wascollected. Solvent was removed by evaporation in a rotary evaporator ata temperature not exceeding 43° C.

1. A process for preparing a cannabinoid-rich extract from cannabisplant material or a primary extract thereof loaded onto an inert matrixmaterial, comprising contacting the cannabis plant material or primarysolvent extract with a heated gas at a temperature which is greater than100° C. and sufficient to volatilise one or more cannabinoids but doesnot cause pyrolysis of the cannabis plant material or primary solventextract thereby volatising one or more cannabinoids to form a vapour,and condensing the vapour to form an extract rich in cannabinoids.
 2. Aprocess according to claim 1 wherein the extract rich in cannabinoids issubstantially free of ballast.
 3. A process according to claim 2 whereinthe extract rich in cannabinoids is substantially free of fats, waxes,carbohydrates, proteins and sugars.
 4. A process according to any of thepreceding claims wherein the extract rich in cannabinoids issubstantially free of terpenes.
 5. A process according to any of thepreceding claims wherein the extract rich in cannabinoids issubstantially free from waxes, sterols and other lipid solublecomponents which characterise solvent extracts.
 6. A process accordingto any of the preceding claims wherein the cannabinoid-rich extract isrich in THC.
 7. A process according to any of claims 1 to 5 wherein thecannabinoid-rich extract is rich in CBD.
 8. A process according to anyof the preceding claims wherein the heated gas is forced upwardlythrough the cannabis plant material, which is retained in a perforatedcontainer, or the primary solvent extract.
 9. A process according to anyof the preceding claims wherein the heated gas is blown onto thecannabis plant material or primary solvent extract.
 10. A processaccording to any of the preceding claims wherein the cannabis plantmaterial or primary solvent extract is subjected to continuousagitation.
 11. A process according to claim 10 wherein the continuousagitation is effected by subjecting the cannabis plant material orprimary solvent extract to a rotary action.
 12. A process according toany of claims 1 to 9 wherein the cannabis plant material or primarysolvent extract is presented to the heated gas in a counter-currentmanner.
 13. A process according to any of the preceding claims whereinthe cannabis plant material is freshly harvested plant material and theprocess further includes a pre-treatment step in which the cannabisplant material is contacted with a heated gas at a temperature which issufficient to dry the cannabis plant material.
 14. A process accordingto any one of claims 1 to 13 wherein the heated gas is a reducing gas ora non-oxidising gas.
 15. A process according to claim 14 wherein thereducing gas is nitrogen, carbon dioxide, helium or argon.
 16. A processaccording to claim 14 wherein the non-oxidising gas is dry steam.
 17. Aprocess according to claim 14 wherein the reducing gas is steam to whichhas been added sodium metabisulphite in a quantity sufficient to produce10-500 parts of sulphur dioxide per million parts of the cannabis plantmaterial or primary solvent extract.
 18. A process according to any oneof the preceding claims wherein the vapour is treated to remove anyparticulate matter prior to the condensation step.
 19. A processaccording to any of the preceding claims wherein the temperature of theheated gas used to volatilise the cannabinoids is selected to effectdecarboxylation of cannabinoid acids present to free cannabinoids and tovolatilise the free cannabinoids.
 20. A process according to claim 19wherein the temperature of the heated gas used to volatilise thecannabinoids is in the range of from 105° C. to 450° C.
 21. A processaccording to claim 20 wherein the temperature of the heated gas used tovolatilise the cannabinoids is in the range of from 105° C. to 225° C.22. A process according to claim 21 wherein the cannabis plant materialor primary solvent extract is a high CBD cannabis plant or a primarysolvent extract thereof and the temperature of the heated gas used tovolatilise the cannabinoids is in the range of from 120° C. to 140° C.23. A process according to claim 21 wherein the cannabis plant materialor primary solvent extract is a high THC cannabis plant or a primarysolvent extract thereof and the temperature of the heated gas used tovolatilise the cannabinoids is in the range of from 105° C. to 120° C.24. A process according to any one of claims 1 to 19 wherein thetemperature of the heated gas used to volatilise one or moreconstituents of the natural product is varied in two or more discretesteps.
 25. A process according to claim 24 which comprises contactingthe cannabis plant material or primary solvent extract with a heated gasat a first temperature and then with a heated gas at a secondtemperature which is greater than the first temperature, greater than100° C. and sufficient to volatilise one or more cannabinoids but doesnot cause pyrolysis of the cannabis plant material or primary solventextract, and condensing any vapour formed at the first and/or the secondtemperature.
 26. A process according to claim 25 wherein vapours formedat the first and the second temperatures are condensed and collected inseparate fractions.
 27. A process according to claim 25 or 26 whereinthe cannabis plant material or primary solvent extract is a high CBDcannabis plant or primary solvent extract thereof, the first temperatureis in the range of from 125° C. to 150° C., and the second temperatureis in the range of from 175° C. to 200° C.
 28. A process according toclaim 25 or claim 26 wherein the cannabis plant material or primarysolvent extract is a high THC cannabis plant or primary extract thereof,the first temperature is in the range of from 60° C. to 90° C., and thesecond temperature is in the range of from 130° C. to 175° C.
 29. Acannabinoid-rich extract which is substantially free of volatileterpenes, has a high content of cannabidiol (CBD) and wherein themajority of the cannabinoids are present in the decarboxylated neutralform, said extract having a profile by gas chromatographic analysissubstantially as illustrated in FIG. 6 fraction B, FIG. 7 fraction B,FIG. 8 fraction A or FIG. 8 fraction B.
 30. A cannabinoid-rich extractaccording to claim 29 which has a profile by gas chromatographicanalysis substantially as illustrated in FIG. 8, fraction A.
 31. Acannabinoid-rich extract which is substantially free of volatileterpenes, has a high content of tetrahydrocannabinol (THC) and whereinthe majority of the cannabinoids are present in the decarboxylatedneutral form, said extract having a profile by gas chromatographicanalysis substantially as illustrated in FIG. 10, fraction B.
 32. Acannabinoid-rich extract which is substantially free of volatileterpenes and which comprises about 98% tetrahydrocannabinol (THC), 2.5%cannabidiol (CBD), 0.5% cannabinol (CBN) and only trace amounts oftetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) andballast.
 33. A cannabinoid-rich extract which is substantially free ofvolatile terpenes and which comprises about 98% cannabidiol (CBD), 1.5%tetrahydrocannabinol (THC), 0.5% cannabinol (CBN) and only trace amountsof tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) andballast.
 34. A cannabinoid-rich extract which is substantially free ofvolatile terpenes and has a ratio of tetrahydrocannabinol(THC):cannabinol (CBN) in the range of from 12.6:1 to 5.5:1 and a Δ⁸tetrahydrocannabinol content of less than 0.7%.